Pharmacological effects of gallic acid in health and diseases: A mechanistic review

Objective(s): Gallic acid is a natural phenolic compound found in several fruits and medicinal plants. It is reported to have several health-promoting effects. This review aims to summarize the pharmacological and biological activities of gallic acid in vitro and animal models to depict the pharmacological status of this compound for future studies. Materials and Methods: All relevant papers in the English language were collected up to June 2018. The keywords of gallic acid, antioxidant, anticancer, antimicrobial, gastrointestinal-, cardiovascular-, metabolic-, neuropsychological-, and miscellaneous- diseases were searched in Google Scholar, PubMed, and Scopus. Results: Several beneficial effects are reported for gallic acid, including antioxidant, anti-inflammatory, and antineoplastic properties. This compound has been reported to have therapeutic activities in gastrointestinal, neuropsychological, metabolic, and cardiovascular disorders. Conclusion: Current evidence confirms the pharmacological and therapeutic interventions of gallic acid in multiple health complications; however, available data are limited to just cellular and animal studies. Future investigations are essential to further define the safety and therapeutic efficacy of gallic acid in humans.


Introduction
The term "phytochemical" points to a vast range of biologically active natural compounds with valuable pharmaceutical and nutritional properties. Phenolic compounds are a group of phytochemicals with at least one hydroxylated benzene ring. The members of this large and diverse group of chemical compounds are usually classified based on the number of carbon atoms in their structures. Simple phenolics, phenolic acids, acetophenones, cinnamic acid derivatives, coumarins, chromones, chalcones, aurones, flavonoids, anthocyanins, betacyanins, benzophenones, xanthones, stilbenes, quinones, lignans, lignins, tannins, and phlobaphenes are the main subgroups of natural phenolic compounds (1).
Phenolic acids are an important and abundant subgroup of phenolic compounds with the basic chemical structure of C 6 -C 1 (hydroxybenzoic acids) or C 6 -C 3 (hydroxycinnamic acids), consisting of a phenolic ring and a carboxyl substituent. The shikimic acid or phenylpropanoid pathway of plant metabolism usually regulate the biosynthesis of phenolic acids. In some cases, phenolic acids are the precursor of other important phytochemicals, such as tannins, coumarins, benzoquinones, and naphthoquinones. Caffeic acid, ferulic acid, p-hydroxybenzoic acid, protocatechuic acid, vanillic acid, salicylic acid, and gallic acid are the most common members of phenolic acids (1,2).
Today, foodstuff containing phenolic compounds and their metabolites are of the main interest due to their favorable effects on human health. In this case, the positive effect of red wine polyphenols on cardiac health or the protective role of flavonoids against various types of cancer and age-related diseases are important examples (2).
in the plant kingdom. It is a colorless or slightly yellow crystalline compound, with extensive application in the food and pharmaceutical industries. Gallic acid has been isolated from different plant species such as Quercus spp. and Punica spp., via various chromatographical methods; however, from the industrial point of view, gallic acid is produced through the hydrolytic breakdown of tannic acid using a glycoprotein esterase, namely tannase (EC 3.1.1.20) (3).
Gallic acid and its derivatives such as lauryl gallate, propyl gallate, octyl gallate, tetradecyl gallate, and hexadecyl gallate, can inhibit the oxidation and rancidity of oils and fats ascribed to their free radical scavenging and antioxidant nature. Therefore, they can be useful as additives in the food industry (4).
Besides the edible uses of gallic acid and its ester derivatives as flavoring agents and preservatives in the food industry, there are diverse scientific reports on biological and pharmacological activities of these phytochemicals, with emphasis on antioxidant, antimicrobial, anti-inflammatory, anticancer, cardioprotective, gastroprotective, and neuroprotective effects (4). This paper reviews the rtant biological and pharmacological activities of gallic acid in order to provide a clear view of the therapeutic aspects of this valuable phenolic acid. Figure 1 represents the most relevant pharmacological activities of gallic acid and related compounds.

Antimicrobial activity
Structure-activity relationship studies of phenolic acids show that some parameters such as the basic chemical structure, the position, and the number of hydroxyl groups as well as their substituents on the phenolic ring, and the esterification of the carboxyl group, can affect the antimicrobial activity. Generally, hydroxycinnamic acids have higher antibacterial activity compared with hydroxybenzoic acids (5). Hydroxybenzoic acids with a lower degree of hydroxylation in phenol groups, highly methoxylated phenol groups, highly oxidized phenol groups, or ester derivatives with long alkyl chains showed higher antibacterial activities in comparison with their parent structures (5). On the other hand, hydroxybenzoic acids with more free -OH groups on the phenol ring were found more potent against the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) (5)(6)(7)(8)(9).
From the mechanistic point of view, gallic acid can inhibit motility, adherence and biofilm formation of Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus mutans, Chromobacterium violaceum, and Listeria monocytogenes (10)(11)(12). The compound can also disrupt the integrity of the cell membrane in Gram-positive and Gram-negative bacteria and change the charge, hydrophobicity, and permeability of the membrane surface (13). Gallic acid can interfere with the membrane permeability of Campylobacter jejuni and elevate the antibiotic accumulation in the microorganism (14). Moreover, it can disintegrate the outer membrane of Gram-negative bacteria via chelation of divalent cations (15).
In addition to its effects on the bacterial cell membrane, there are some reports on the inhibitory activity of gallic acid against bacterial dihydrofolate reductase and its excitatory activity on topoisomerase IV-mediated DNA cleavage in different bacteria (16). Alkyl gallates can also penetrate the bacterial cell membrane and interfere with the electron transport chain and cellular respiration (17).
Some ester derivatives of gallic acid, i.e., octyl gallate, use the hydrophilic catechol part as a hook to bind to the polar surface of the cell membrane and enter the lipid bilayer using the hydrophobic alkyl part. Subsequently, they act as a nonionic surfactant and interfere with the selective permeability of cell membrane in fungi (17).
In connection with protozoa, gallic acid can bind to the glutamate-gated chloride channels in the nervous system of Caenorhabditis elegans and initiates the hyperpolarization of the cell membranes and excitation of muscles. These events finally result in worm paralysis and death (28).

Anticancer activity
In normal physiological conditions, the cells of a healthy organism are programmed for collaboration and coordination, thereby disruption in cells can evoke different life-threatening diseases, such as cancer. At the cellular level, cancer is defined as an unusual increase of cell division, the resistance of the produced cells to death, and their tendency to invade and metastasize.
The cancerous cells disturb the normal functions of other cells by invasion or metastasis. No matter where the origin of the problem is, the overall quality of life is overshadowed by cancer. According to the official reports of health-and wellness-related organizations, the magnitude of personal and social consequences of cancer is very significant and the investigation of new drugs to control this problem continues (35)(36)(37)(38).
Gallic acid can exert its cytotoxic and antitumor effect via modulation of antioxidant/pro-oxidant balance. In some cases, the compound can control the reactive oxygen species (ROS)-induced carcinogenesis through increasing the activity of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx) and/or by reducing the lipid peroxidation and ROS production. In other cases, gallic acid can induce the cell cycle arrest, autophagy, and apoptosis via activating the caspases pathway and ROS generation. In addition, it can inhibit the invasion and metastasis by decreasing the matrix metalloproteinase expression and activity (39)(40)(41)(42)(43).
Moreover, some derivatives of gallic acid, such as isobutyl gallate-3,5-dimethyl ether and methyl gallate-3,5-dimethyl ether, are able to reduce the tumor size and increase the survival rate in in vivo models of cancer (44). Gallic acid regulates the cell-cycle-related proteins such as cyclin A, cyclin D1, and cyclin E, and slow down the cell division by induction of the p27KIP enzyme and inhibition of CDK activity (45). In the case of hepatocellular carcinoma, gallic acid decreased the tumor size and the serum level of tumor marker enzymes such as aspartate transaminase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) by inhibiting the proliferation of hepatic cells (46) ( Table 1).

Gastrointestinal diseases
Gallic acid protects the mucosal layer of the gastrointestinal tract from ulcer via different mechanisms by reducing the acid secretion, inducing the release of endogenous antioxidant agents and defensive factors (i.e. SOD, CAT, endothelial nitric oxide synthase (e-NOS) and prostaglandin E2 (PGE2)), as well as decreasing oxidative stress and lipid peroxidation. In addition, gallic acid has been associated with several other beneficial pathways including reduction of the expression of pro-inflammatory mediators (i.e., tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (i-NOS)), up-regulation of the pro-angiogenesis factors (i.e., Von Willebrand factor (vWF) VIII, mucosal hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF)), promotion of angiogenesis, and inhibition of the expression of apoptosis parameters (i.e., caspase-3 and caspase-9) (47-49) ( Table 1).
Beside the gastroprotective activity, gallic acid ameliorates the hepatotoxic effects of xenobiotic agents by acting as an antioxidant compound that scavenges free radicals, such as ROS, and improves the capacity of antioxidant defense systems including SOD, GST, GPx, CAT, GSH, and cytochrome P450-dependent detoxifying enzymes (52-57) ( Table 1).

Cardiovascular diseases
Myocardial ischemia is defined as a condition that is caused by an imbalance between oxygen supply and demand of the myocardium, of which coronary artery atherosclerosis is known to be the main cause. To decrease the risk of myocardial infarction, the ischemia can be treated using different surgical methods and/or pharmacological agents.
Gallic acid pretreatment decreases the harmful oxidative consequences of myocardial infarction in the context of its antioxidant potency (58), either by increasing the activity of antioxidant enzymes, such as SOD, CAT, GST, and GPx (58) and/or by elevation of the level of non-enzymatic antioxidant agents, such as GSH, vitamin C, and vitamin E (58). All of these activities can inhibit the detrimental effects of free radicals on the integrity and function of myocytes membranes, and consequently, the concentration of serum cardiac biomarkers, including cardiac troponin T (cTnT) and creatine kinase-MB (CK-MB) decreases after infarction (35,58) (Table 1).

Metabolic diseases
Obesity, diabetes mellitus, and hyperlipidemia are the most prevalent metabolic disorders among adults. The ability to store the excess energy in adipocytes and release it in the future is vital for survival. However, genetic susceptibility, excessive energy intake and sedentary lifestyle may provoke increased adipose storage and further cause metabolic disorders.
In metabolic disorders, gallic acid inhibits dietinduced hyperglycemia and hypertriglyceridemia, reduces the size of adipocytes, and protects pancreatic β-cells by inducing the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), a nuclear transcription factor that induces differentiation and insulin sensitivity in adipocytes (59). Gallic acid also increases the cellular glucose uptake via stimulation The compound prevents the diet-induced oxidative stress by stimulating various enzymatic and nonenzymatic antioxidant defenses (60). Gallic acid can up-regulate the hepatic glycolysis enzymes, such as hexokinase, aldolase, and phosphofructokinase, and down-regulate the hepatic gluconeogenesis enzyme, named fructose-1,6-bisphosphatase, in rodents fed a high fructose diet (59-63) ( Table 1).

Neuropsychological diseases
Alzheimer's disease is a cognitive neurodegenerative problem (35), which commonly results in dementia in elderly individuals. Insidious memory loss and progressive dementia over the years are the major clinical presentations of patients. In this disease, the atrophy of the brain starts from the temporal lobe and spreads to the parietal and frontal lobes. In the microscopic scale, plaques of amyloid-β (Aβ) molecules and fibrillary tangles of hyperphosphorylated tau filaments are visible in the nervous system (35).
The protective effect of gallic acid on nerve cells is a controversial issue. On the one hand, gallic acid decreases the Aβ-induced toxicity in cultured cortical neurons of rats via inhibiting Ca 2+ release from the endoplasmic reticulum into the cytoplasm or Ca 2+ influx, inhibiting ROS generation and apoptosis (64). The compound restores the streptozotocin (STZ)-induced cerebellar oxidative stress and cognitive impairment in rats by scavenging free radical molecules such as ROS, inhibiting lipid peroxidation, and stimulating the activity of endogenous antioxidant agents, such as SOD, CAT, and GPx (65). Gallic acid is also able to reverse the scopolamine-induced amnesia in mice, probably through inhibiting oxidative stress and decreasing acetylcholinesterase (AChE) enzyme activity in the brain (66).
On the other hand, gallic acid decreases the viability of PC-12 rat pheochromocytoma cells in the H 2 O 2induced toxicity model (67). In this manner, gallic acid increases the rate of apoptosis via stimulation of the c-Jun N-terminal kinase (JNK) protein, down-regulation of Bcl-2 protein, inducing poly (ADP-ribose) polymerase cleavage, or even increasing intracellular Ca 2+ and ROS generation (67) ( Table 1).
As mentioned earlier, gallic acid can partially neutralize the substance-induced toxicity in the liver and neural system. The beneficial and protective effects of gallic acid on substance-or radiation-induced toxicity in connective tissue, especially bone marrow, renal, reproductive, and respiratory systems have been proven. Almost all of the above-mentioned effects are linked to the antioxidant activity of gallic acid (74)(75)(76)(77)(78)(79)(80)(81)(82).
Topical application of gallic acid prevents the UV-B induced hyperpigmentation and photoaging of mice skin via down-regulating the melanogenic genes such as tyrosinase, increasing the skin hydration and transforming growth factor (TGF)-β1 induced production of procollagen type I and elastin, and decreasing ROS activation, wrinkle formation, and epidermal thickening (83,84) (Table 1).

Conclusion
Studies presented here showed that the most important pharmacological properties of gallic acid are attributed to its antioxidant and anti-inflammatory potentials. In addition, gallic acid is involved in various signaling pathways that regulate the wide range of biological functions including pro-and inflammatory pathways, NO signaling pathway, intrinsic and extrinsic pathways of apoptosis, and NF-κB signaling pathway. Gallic acid and its derivatives demonstrated a broad range of beneficial effects in prevention and/or management of several disorders, also their acceptable safety and stability profiles, make them significant options to be introduced as dietary supplements.

Pharmacological effects of gallic acid and human health
Kahkeshani et al.
Dermal Gallic acid In vitro: normal human dermal fibroblasts exposed to UVB In vivo: hairless mice exposed to UVB In vitro: ↓transcription factor activation protein 1 activity